2-substituted-tetrahydro-halosulfamyl-quinazolinones



United States Patent M 3,458,513 2-SUBSTITUTED-TETRAHYDRO-HALO-SULFAMYL-QUINAZOLINONES Bola Vithal Shetty, Rochester, N.Y., assignor toWallace and Tiernan, Inc., East Orange, N.J., a corporation of DelawareNo Drawing. 'Continuation-in-part of application Ser. No. 517,995, Jan.3, 1966. This application Nov. 2, 1967, Ser. No. 680,043

Int. Cl. C07d 51/48; A61k 27/00 U.S. Cl. 260-256.5 7 Claims ABSTRACT OFTHE DISCLOSURE A 1,2,3,4-tetrahydro-halo-sulfamyl 4 quinazolinonecompound having diuretic properties with low potassium excretion,characterized by having in the 3-position a substituted or unsubstitutedaryl or aralkyl group, and by having in the 2-position a substituted orunsubstituted alkoxy or alkoxyalkyl group.

This application is a continuation-in-part of copending application Ser.No. 517,995, filed Jan. 3, 1966, now U.S. Patent 3,360,518, thedisclosure of which is hereby incorporated by reference.

This invention relates to 1,2,3,4-tetrahydro-6-sulfamyl-3 aryl oraralkyl-4-quinazolinone compounds having diuretic properties, and moreparticularly to such compounds substituted in the 7-position withhalogen or haloalkyl and in the 2-position with alkoxy, alkoxyalkyl, orsuch radicals substituted with halogen, cycloalkyl or phenyl.

In applicants aforesaid copending application, now U.S. Patent No.3,360,518 there are disclosed, but not claimed, compounds of the abovetype as diuretics. However, these compounds were so different from thecompounds claimed that further work on the compounds disclosed andrelated compounds was deemed advisable before attempting to obtainpatent coverage.

In accordance with this invention, 1,2,3,4-tetrahydro- 7-halo orhaloalkyl-6-sulfamyl-3 aryl or aralykyl-4-quina- Zolinone compounds havein the 2-position alkoxy, cycloalkoxy, phenylalkoxy or such groupshaving halogen substituted therein.

The compositions of this invention are preferably of the followingformula:

in which X is halogen or trifluoromethyl, Y is hydrogen or loweralkyl, Ris hydrogen, loweralkyl, or phenylloweralkyl, R is loweralkoxy,loweralkoxyloweralkyl, halogen substituted loweralkoxy or halogensubstituted loweralkoxyalkyl, lowercycloalkylloweralkoxy,lowercycloalkylloweralkoxyloweralkyl, or one or both substituted in thealkylalkoxy or cycloalkyl group with a halogen or in the cycloalkylgroup with a loweralkyl, phenylloweralkoxy orphenylloweralkoxyloweralkyl, R and R are any of the members of hydrogen,loweralkyl, loweralkoxy or loweralkoxyloweralkyl; x is hydrogen,loweralkyl, hydroxy, loweralkoxy, loweralkoxyloweralkyl, NH SO NH halo-3,458,513 Patented July 29, 1969 gen or trifluoromethyl, y and z are anyof x, and n is an integer from 0-4.

The terms loweralkyl and loweralkoxy mean radicals having not more than8 carbon atoms in a straight alkyl chain, and the term lowercycloalkylmeans a cycloalkyl having not more than 8 carbon atoms in the cycloalkylring.

In the above formula X is preferably chlorine or trifluoromethyl, butbromine and the other halogens are not precluded. R is preferablyhydrogen, but lower alkyls such as methyl, ethyl, propyl, and isopropylmay be used. R is preferabl) methoxy or methoxymethyl. R is preferablyhydrogen with R being methyl, or R is hydrogen with R being methyl. x,y, and 1 may be any of the stated radicals in one or more of the ortho,meta or para positions. Preferably x is methyl in the ortho position,also where sulfamyl is used it is preferably present in the meta or paraposition with methyl in the ortho position.

Specific suitable compounds of the above formula include2-methoxy-3-o-tolyl-6-sulfamyl-7-chloro-1,2,3,4-

tetrahydro-4-quinazolinone;Z-methoxy-3-o-tolyl-6-sulfamyl-7-trifluoromethyll,2,3,4-tetrahydro-4-quinazolinone;2-ethoxy-3-o-tolyl-6-sulfamyl-7-trifluoromethyll,2,3,4-tetrahydro-4-quinazolinone;2-ethoxymethyl-3-o-tolyl-6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone;2-methoxy-3-o-tolyl-6-methylaminosulfonyl-6-chloro-1,2,3,4-tetrahydro-4-quinazolinone;2-methoxy-3-(p-chlorophenyl)-6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone;2-methoxy-3-o-tolyl-6=methylaminosulfonyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone;2-methoxy-3-phenyl-6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone; 2-methoXy-3- 2'-methyl-3-chlorophenyl) -6-sulfamyl- 7-chloro-1,2,3,4-tetrahydro-4-quinazolinone;2-methoxy-3-(p-chlorophenyl)-6-methylaminosulfonyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone; 2-methoxy-3- 2-methylbenzyl-6-sulfamyl-7-chloro- 1,2,3,4-tetrahydro-4-quinazolinone;2-phenylmethoxy-3-o-tolyl-6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone;2-ethoxymethyl-3-o-tolyl-6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone;2-InethoXybutyl-3-o-to1yl-6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone;2-methoxypropyl-3-o-tolyl-6-sulfamyl-7-trifluoromethyl-1,2,3,4-tetrahydro-4-quinazolinone;2-phenylmethoXymethy1-3-o-tolyl-6-sulfamy1-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone;Z-chloromethyoxy-3-o-tolyl-6-sulfamyl-7-chloro- 1,2,3,4-tetrahydro-4-quinazolinone;2-dichloromethoxy-3-o-tolyl-6-sulfamyl-7-chloro- 1,2,3,4-tetrahydro-4-quinazolinone;2-trichloromethoxy-3-o-tolyl-6-sulfamy1-7-chloro- 1,2,3,4-tetrahydro-4-quinazolinone;2-benzylmethoxyethyl-3-o-tolyl-6-sulfamy1-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone; 2-methoxy-3- (o-hydroxphenyl-6-sulfamyl-7-chloro- 1,2,3,4-tetrahydro-4-quinazolinone;

2-methoxy-3- o-methoxyphenyl) -6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-4-quinaZolinone;

2-methoxy-3- (p-aminophenyl) -6-sulfamyl-7-chl0ro-1,2,3,4-tetrahydro-4-quinazolinone;

8,458,513 .5 6 The following example illustrates the compounds andII.Experimental procedures methods of Preparatwn: The basic assay methodwas that of Lipschitz, Hadidian,

EXAMPLE I and Kerpcsar, J. Pharm. and Exp. Therap. 77:97. Briefly,Synthetic Scheme the method is as follows: four over-night fasted,Spraguell l Preparation of the compound 2-methoxymethyl-3-o-toly1-Dawley, albino rats were placed in each of ten stainless6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazo1inone 40 steel, nitricacid-washed metabolism cages. Two cages of r -4 1 1f 1 N t 1 1)benzamide animals were used as controls and were subjected to all(33.92.) was suspended in 300 ml. acetic acid and heated p h P (105mgYvlth compouhds- All rats to 70. Concentrated sulfuric acid (0.7 ml.)was add d cerved an initial LP. hydration of 2.5 cc. de-ionized waterand then 1,2,2-trimethoxyethane (14 g.) was added drop- P 100 grams ofanimal Weight This Was fOllOWed 2 wise during 3 minutes. The solidrapidly dissolved and the 4.5 hours later y 0f 09% Saline P 100 ofanimal temperature was maintained for 10 minutes. The heat Weight givenby stomach tube. With this saline load, the source was removed and afterminutes the reaction was compounds dissolved as 2% solutions in 0.2 NNaOH cooled to room temperature and poured into 1 liter of wawere alsoadministered. The amount of NaOH per 100 g. ter. The precipitate wasfiltered and dried to glve 3 gof of rat was kept constant. Controlanimals received all subcrude product. The product was refluxed withchloroform stances except th compounds and fi e e and e h Pllflfied yChromatography Urine was collected under light mineral oil for 4 hourslowed by recrystalhzation from alcohol. M.P. 154-6. and analyzed forvolume [N33,] [Kir] and Calculated for c1qH13ClN304S+1-1% H20: C, H,4.69; N, 10.50. Found: C, 51.05; H, 4.47; N, 10.70.

The other compounds of this invention can be made by modification ofingredients and quantities of the above example as is well understood bythose skilled in the art. Compound 751 263 (Lot #751463) a WhltePowdfiry From pharmacology tests run on 2-methoxymeth 1-3 Substance, wasreceived from the Pharmaceutical Chemo t01y1 6 Su1famy1 7 ch1Oro 13,3,4tetrahydro 4(3H) istry Department in an amber bottle and stored in arefrigquinazolinone (compound 751-263) and other indications efator-HYdYPChIOI'OthiaZidB Lot and analogy applicant states that the compoundsof this Was Obtamed from Merk Sharp and Dohme Research Appropriatecalculations were done to convert the output of urinary volume, Na+,K*', and Cl into Incl. or mceq./kg./ 4 hr.

invention coming under the claims are elfective diuretics, Laboratoryand TefIl-igeratedsaluretics, and antihypertensives with low toxicity.For ex- The 10565 in gadministered were as follows: ample, the followingis a summary of the pharmacology HCTZI 751-2531 10-00, on compound8751-263: 100.00.

I""SummaIy III.-Experimental results Compound 8751-263(2-methoxymethyl-3-(otolyl)-6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone) was The Variousurinary p Calculated as described compared with hydrochlorothiazide forits diuretic, natruiabove, Were Plotted against the 10g of the doses-These retic and kaliuretic properties by a rat assay. dose-responsecurves are presented in FIGURES 1, 2, 3,

The diuretic and natriuretic properties of this comand 4 for volume,Na+, K and Cl" respectively. pound appear to be equivalent to those ofhydrochloro- For approximate potency comparisons, the distancebethiaziide. The Na+ to K+ output ratio is apparently more tween thesteep portions of the dose-response curves were favorable than that ofhydrochlorothiazide. measured. Assigning a value of 1 for the responseto 7 HCTZ, the potencies of 751-263 compared with HCTZ for the variousparameters of renal function are as follows:

Volume Approximately equal. Na+ 3 From these data compound 751-263appears to be as potent a diuretic and natriuretic agent ashydrochlorothiazide with evidence of a more favorable Na+ to K+ outputratio.

No overt evidence of toxicity was seen in the te animals.

In the preceding specification the temperature, wherever given, are indegrees centigrade.

Various modifications of the structural formula on page 1 of thespecification may be made, such as, for example, has been done for othertetrahydro-7-halo-6- sulfamyl-4-quinazolinones known to the art, withoutdeparting from the spirit of the invention which is concernedparticularly with the aryl and alkaryl group on the 3 position, andalkoxy, cycloalkoxy, or phenylalk'oxy in the 2 positions.

Likewise, therapeutically effective salts of the compounds of theinvention may be made by methods known to the art, and are usefuldiuretics. For example, the sulfamyl group will react with bases to givesodium, potassium or ammonium salts of the quinazolinone compound. Thebasic nitrogen of the quinazolinone can be reacted with acids such ashydrochloric, maleic, tartaric, and the acidic ion exchange resins suchas carboxylic acid, phosphonic acid, and sulfonic acid cation exchangeresins to give the therapeutically effective and nontoxic salts of thequinazolinone compound.

I claim:

1'. A compound of the formula:

or any of their pharmaceutically acceptable salts, in which X is halogenor trifiuoromethyl, Y is hydrogen or loweralkyl, R is hydrogen orloweralkyl, or phenylloweralkyl, R is loweralkoxy,loweralkoxyloweralkyl, halogen substituted loweralkoxy orloweralkoxyloweralkyl, lowercycloalkylloweralkoxy,lowercycloalkylloweralkoxyloweralkyl or one or both of said radicalssubstituted in the Approximately equal.

alkyl, alkoxy or cycloalkyl groups with a halogen, or in the cycloalkylgroup with a loweralkyl; phenylloweralkoxy, orphenylloweralkoxyloweralkyl, R and R are any of the members of hydrogenloweralkyl, loweralkoxy, or loweralkoxyloweralkyl, x is hydrogen,loweralkyl, hydroxy, loweralkoxy, loweralk-oxyloweralkyl, NH sulfamyl,halogen, or trifluoromethyl, y and z are any of the members of x, and nis an integer from 0-4.

2. The compound of claim 1 wherein R is a loweralkoxy orloweralkoxyloweralkyl.

3. The compound of claim 1 wherein X is chlorine, Y is hydrogen, R ishydrogen, R is methoxy, R and R are hydrogen, at is orthomethyl, both yand z are hydrogen, and n is 0.

4. The compound of claim 1 wherein X is chlorine, Y is hydrogen, R ishydrogen, R is methoxymethyl, R and R are hydrogen, x is orthomethyl,both y and z are hydrogen, and n is 0.

5. The compound of claim 1 wherein X is chlorine, Y is hydrogen, R ishydrogen, R is chloromethoxymethyl, R and R are hydrogen, x isorthomethyl, both y and z are hydrogen, and n is 0.

6. The compound of claim 1 wherein X is chlorine, Y is hydrogen, R ishydrogen, R is methoxymethyl, R and R are hydrogen, x isorthotrifiuoromethyl, both y and z are hydrogen, and n is 0.

7. The compound of claim 1 wherein X is trifiuoromethyl, Y is hydrogen,R is hydrogen, R is methoxymethyl, R and R are hydrogen, x isorthomethyl, both y and z are hydrogen, and n is 0.

References Cited UNITED STATES PATENTS 3,133,918 5/ 1964 MacPhillamy eta1. 3,291,794 12/ 1966 Huebner. 3,297,693 l/ 1967 De Stevens et a1.3,324,121 6/ 1967 Sprague. 3,336,305 8/1967 Scarborough et a1. 3,336,3208/1967 Doebee et al. 3,341,520 9/ 1967 Pfenninger. 3,360,518 12/1967Shetty 260-256.5

FOREIGN PATENTS 692,082 4/1967 Belgium.

ALEX MAZEL, Primary Examiner R. J. GALLAGHER, Assistant Examiner US. Cl.X.R. 424-251 Dated July 29, 1969 Patent No. 3 458 513 Bola Vithal Shettyears in the above-identified patent corrected as shown below:

Inventor (s) It is certified that error app and that eaid Letters Patentare hereby Claim 1, column 7, lines 50 and 51, insert a comma after"lowercycloalkylloweralkoxyloweralky1" and in column 8, line 4, insert acomma after "hydrogen".

SIGNED AND SEMED DEC2-1959 Anest:

EdwlnllLFletcherJr.

WILLIAM E. SGHUYLER, JR- Auesung Of Domissioner of Patents

